Endogenous GLP-1 as a key self-defense molecule against lipotoxicity in pancreatic islets

摘要

The number of pro-α?cells is known to increase in response to β?cell injury and these cells then generate glucagon-like peptide-1?(GLP-1), thus attenuating the development of diabetes. The aim of the present study was to further examine the role and the mechanisms responsible for intra-islet GLP-1 production as a self-protective response against lipotoxicity. The levels of the key enzyme, prohormone convertase?1/3?(PC1/3), as well as the synthesis and release of GLP-1 in models of lipotoxicity were measured. Furthermore, islet viability, apoptosis, oxidative stress and inflammation, as well as islet structure were assessed after altering GLP-1 receptor signaling. Both prolonged exposure to palmitate and a high-fat diet facilitated PC1/3 expression, as well as the synthesis and release of GLP-1 induced by β?cell injury and the generation of pro-α?cells. Prolonged exposure to palmitate increased reactive oxygen species?(ROS) production, and the antioxidant, N-acetylcysteine?(NAC), partially prevented the detrimental effects induced by palmitate on β?cells, resulting in decreased GLP-1 levels. Furthermore, the inhibition of GLP-1 receptor?(GLP-1R) signaling by treatment with exendin?(9-39) further decreased cell viability, increased cell apoptosis and caused a stronger inhibition of the β?cell-specific transcription factor, pancreatic duodenal homeobox?1?(PDX1). Moreover, treatment with the GLP-1R agonist, liraglutide, normalized islet structure and function, resulting in a decrease in cell death and in the amelioration of β?cell marker expression. Importantly, liraglutide maintained the oxidative balance and decreased inflammatory factor and p65 expression. Overall, our data demonstrate that an increase in the number of pro-α?cells and the activation of the intra-islet GLP-1 system comprise a self-defense mechanism for enhancing β?cell survival to combat lipid overload, which is in part mediated by oxidative stress and inflammation.